Sortase A anchoring mechanism

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DESCRIPTION (provided by applicant): Gram-positive bacteria adhere to specific tissues in animals using the surface proteins displayed on their cell wall. These surface proteins promote bacterial adhesion, evasion of the host immune system and invasion of the host organism. The enzymes responsible for attaching these proteins to the cell wall are called sortases and they are found in all gram-positive bacteria. The focus of this proposal is to study sortase A (SrtA) from Staphylococcus aureus. To obtain a better understanding of the universal anchoring mechanism of sortases we will design and test the enzymatic effectiveness of several inhibitors of SrtA. We also propose to elucidate the structure of the SrtA-inhibitor complex by using NMR spectroscopy. We will identify the amino acids that are important for catalysis and substrate binding by introducing single amino acid mutations in SrtA. The knowledge gained from this study will hopefully lead to ways of disabling this anchoring mechanism and thereby preventing bacterial infection. Work leading to the creation of anti-infective agents against pathogenic bacteria should be prioritized especially in an era where bacteria have developed a resistance to many commonly used antibiotics.